tbuckley/cabot-search huggingface dataset:
Abstract 13927: AAV Gene Therapy to Treat Underlying Cardiac Biomechanical Defects in <i>Lmna</i> Dilated Cardiomyopathy Improves Lifespan and Preserves Ejection Fraction in <i>Lmna</i> DCM Mouse Model
Authors: Hendrikje Werner, Esther S Gan, Connie Y Loh, Nyein Thet Khaing, Jinqiu Zhang, Mervyn Ong, Brian Burke, Yann Chong Tan, Colin L Stewart, Yin Loon Lee
Journal: Circulation (2022)

Mutations in the LMNA gene are the second most common cause of genetic dilated cardiomyopathies (DCMs) with a prevalence of ~1/12500. Adeno-associated virus (AAV) gene therapies are a promising treatment modality for genetic disease. However, the autosomal dominant, gain-of-function mutations underlying LMNA DCM preclude standard gene replacement approaches. To understand LMNA DCM, we previously generated a mouse model that exhibits reduced ejection fraction, dilation of ventricular inner dimensions and increased cardiac fibrosis, surviving for only ~40 days after cardiac-specific deletion of the Lmna gene. We propose that the mutant LMNA gene weakens the structural integrity of the nucleus, making it vulnerable to biomechanical forces generated by contracting cardiomyocytes, which ultimately results in nuclear damage and a decline in cardiac function. Our gene therapy, AAV9-cTnT-GSLA01, prevents nuclear damage and disease in our Lmna DCM model by reducing biomechanical forces transmitted to the nucleus. To determine if we can treat, rather than prevent, Lmna DCM, we injected animals with AAV9-cTnT-GSLA01 at 1x10 14 vg/kg at different timepoints (21, 17, 14 and 1 day(s)) after induction of Lmna deletion. Treatment with AAV9-cTnT-GSLA01 17 days post Lmna deletion resulted in lifespan extension to 108 days (P= 0.0002), while earlier intervention at day 14 or day 1, improved lifespan to 122 and 208 days respectively (P = 0.0002, P= 0.0035). To address dose dependency of AAV9-cTnT-GSLA01, we delivered the vector at 5x10 13 vg/kg, 1x10 14 vg/kg, and 2x10 14 vg/kg at 17 days after Lmna deletion. Lifespan was extended from 40 days in untreated mice to 51.5 (P = 0.0135), 67.5 (P &lt; 0.0001), and 103.5 days (P &lt; 0.0001) respectively. The progressive decline of ejection fraction in these mice was attenuated in a dose-dependent manner. Thus, the positive effect of AAV9-cTnT-GSLA01 on lifespan and cardiac function in Lmna DCM mice is enhanced with increasing dose and transgene expression. Initial optimisation of the therapeutic expression cassette appears to improve lifespan extension significantly. AAV9-cTnT-GSLA01 is a novel gene therapy approach that promises to address the underlying cause of LMNA DCM.
Abstract 14108: Cisplatin-Induced Cardiac Macrophage Inflammatory Programs Unveiled With Single Cell Sequencing
Authors: Hua Pan, XueYing Song, Alex Rajewski, Samuel A Wickline
Journal: Circulation (2022)

Introduction: Cisplatin is used broadly in first-line chemotherapy regimens prescribed to ~20% of cancer patients. It is known that cisplatin treatment induces inflammatory cardiotoxicity, but the specific molecular sequellae in resident or trafficking cardiac macrophages remain to be elucidated. We hypothesized that single cell analysis of cardiac macrophage populations after cisplatin treatment would shed new light on the molecular mechanisms of inflammation in the heart induced by the cisplatin treatment and suggest new approaches to mitigate cisplatin induced cardiotoxicity. Methods: A mouse model was generated by i.p. injection of 25 mg/kg cisplatin to C57BL/6 mice. Saline injection served as control. Hearts were collected 48 hours post injection and single cell suspensions were produced before libraries were created using 10X genomics Chromium Next GEM Single Cell 3’ Reagent Kits (v3.1) before sequencing. CellRanger was used for processing single cell RNASeq outputs, followed by secondary Seurat analysis and DEG, KEGG pathway and TRANSFAC analysis on macrophages. Results: DEG analysis demonstrated that cisplatin treatment significantly inhibited expression of MHC class II-associated genes (H2-AB1, H2-EB1, H2-AA, H2-DMA, H2-DMB1) (Fig A and B). KEGG pathway analysis suggested that cisplatin treatment upregulated genes involved in IL-17 signaling pathway (LCN2, S100a9, S100a8) (Fig C and D). TRANSFAC analysis identified NF-κB as the only significantly upregulated transcription factor caused by cisplatin treatment with predicted binding sites of KCCAGANWN (NF-1B), GGGANTTTCCNN (RelA-p65), and KGGRNTTTCCC (RelA-p65). Conclusions: Reduced MHC-II gene expressions by cisplatin might upregulate self-repair pathways to promote macrophage efferocytosis and wound healing. The pro-inflammatory NF-κB and IL-17 signaling pathways represent potential therapeutic targets for mitigating cisplatin induced cardiac inflammation.
Abstract 14867: Examining Effects of a Physical Activity Intervention on Exercise Capacity and Cardiovascular Function Among Patients With Lymphoma and Breast Cancer Undergoing Treatment
Authors: Alexander R Lucas, Juliana Costa, Peter H Brubaker, Shannon L Mihalko, Rakhee Vaidya, Mary Beth Seegars, Jennifer H Jordan, Alexandra Marshall, Jeremy O Via, Robert L Franco, Amy Ladd, Ralph Dagostino, William G Hundley
Journal: Circulation (2022)

Introduction. Patients receiving serial outpatient infusion treatment for lymphoma or breast cancer (BC) with potentially cardio-toxic chemotherapeutic regimens may experience declines in left ventricular ejection fraction (LVEF) and exercise capacity. This study sought to determine if a physical activity intervention (PAI) administered during cancer treatment could attenuate deterioration of exercise capacity and LVEF. Methods. Across two NCI funded cancer centers, we randomized (2:1) 34 participants to a home-based PAI or healthy living education intervention (HLI) within 6 weeks of initiating curative therapies for stage I-IV Hodgkin’s, non-Hodgkin’s lymphoma, or stage I-III BC (NCT01719562). Training programs were tailored by treatment and functional status and adapted for remote delivery during COVID-19. Exercise capacity was determined via cardiopulmonary exercise test (peak VO 2 [ml/kg/min]) and LVEF (%) was determined by magnetic resonance imaging at baseline, 3, and 6 months. Separate linear mixed-effects regression models controlling for baseline values examined changes in peak VO 2 and LVEF by time and treatment group. Results. Demographics were similar between the two arms (PAI vs. HLI, 52.4 [16.3] vs. 56.8 [12.7] years of age [SD]; 69% vs. 75% white; and 57.7% vs. 50% female). Peak VO 2 increased at 3 (+1.15 ml/kg/min [CI: -1.46 - 3.77]) and 6 months (+3.88 ml/kg/min [CI: 0.79 - 6.96]) in the PAI arm, while the HLI arm increased slightly at 3- (+0.67 ml/kg/min [CI: -5.14 - 6.48]) but not 6 months (-0.83 ml/kg/min [CI: -5.99 - 4.33]). LVEF declined slightly at 3 months in the PAI (-2.29% [CI: -4.83 - 0.25]) but not HLI arm (3.05.% [CI: -2.49 - 8.60]), while at 6 months, the PAI arm had returned to baseline LVEF (-0.58% [CI: -4.30 - 3.14]) and the HLI arm declined slightly (-1.76% [CI: -7.23 - 3.71]). Conclusions. This pilot RCT suggests the importance and utility of home-based physical activity during cancer treatment in protecting against expected declines in exercise capacity and LVEF. These results highlight the need for larger randomized trials that examine the effects of lifestyle interventions administered during treatment to improve quality of life and to support long term cardiovascular health in cancer survivors.
Abstract 13323: A Survey Study of the Adherence to the 2020 Acc/aha Heart Failure Guideline in Low-Middle Income Countries (Gaza Strip as an Example)
Authors: Mahmoud Alsaiqali, Ghassan Al-Saikaly, Mohammad AboAbdo, Mohammed Mezeid, Zakaria Mansour, Alaa Al Zaharna, Mohammed Al-Sadawi, Mohammed Habib, Mohammed Mhanna
Journal: Circulation (2022)

Introduction: Acute heart failure is associated with higher post-discharge mortality, especially in low-middle income countries (LMIC). There are limited studies on adherence to the recommended post-discharge care guidelines in these settings. The study assessed adherence to the 2020 ACC/AHA inpatient heart failure performance and quality measure in Gaza Strip, Palestine. Methods: The study was a cross-sectional survey study. We chose a stratified random sample from the three different geographical areas across Gaza Strip with numbers proportional to the size of each region. Patients selected were adults (&gt;18 years) admitted to the various hospitals for acute decompensated heart failure between 4/2021 and 12/2021. We collected data through chart review. Measures were β blockers, ACEi/ARB and MRA prescription, and outpatient follow-up. Results reported as proportion with 95% CI. Results: The sample size was 155 patients. The mean age was 64 years. 59% were males. The mean length of stay was 2.8 days. β blockers were prescribed to 85.1% [79.5,90.8] of patients. For ACEi/ARB use, it was 42.7% [34.9,50.5]. For MRA, after excluding ineligible patients, it was prescribed in 48.5% [39.9, 57.2]. None of the patients were prescribed hydralazine/nitrate. Only 30.1% [ 23.6, 38.1] of patients had an outpatient appointment. The median time between discharge and appointment date was 22 days. Only 9.7% [5.0,14.3] of patients were discharged with all quality measures fulfilled. Conclusions: There are considerable gaps in the post-discharge care of heart failure patients in the Gaza Strip. There is a need to develop local care guidelines to improve care.
Abstract 12951: Electrical and Calcium-Dependent Mechanisms That Contribute to Increase the Risk for Atrial Fibrillation in Obesity
Authors: Eleonora Savio-Galimberti, Tiffany Scotto, David Wasserman, Prince Kannankeril
Journal: Circulation (2022)

Obesity (OB) is an independent predictor for atrial fibrillation (AF), but mechanisms by which OB increases AF risk remain poorly characterized. We hypothesized that OB modulates AF risk through electrical remodeling and impaired Ca 2+ dynamics that can be reversed after weight loss (WL). Using transesophageal rapid pacing we characterized AF inducibility and burden in lean, OB, and OB mice that lost 20% of body weight after modified vertical sleeve gastrectomy. Local field fluorescence microscopy was used to simultaneously record action potentials (APs) (di-8-ANEPPS or glass microelectrodes) and Ca 2+ transients (CaT) (Rhod-2) in Langendorff heart preparations. We evaluated AP duration (APD) dependency of frequency from 4 to 14 Hz (1 Hz incremental steps). AP parameters analyzed included APD30, APD50, APD90 and spontaneous arrhythmogenic events. We assessed Ca 2+ dynamics by studying CaT and fractional sarcoplasmic reticulum Ca 2+ release in the absence and presence of ryanodine (Ry) and thapsigargin (Tg). Since CaT Ry+Tg represents sarcolemmal Ca 2+ influx, we calculated the gain of Ca 2+ induced Ca 2+ release (CICR gain ) as the ratio between CaT in the absence and presence of Ry+Tg. Experiments were done in the presence of blebbistatin at 37° C. Mean±SE, t-test. After burst pacing, both AF prevalence and burden were higher in OB mice vs lean (94 % vs 47 %, 227±19 vs 20±1.2 s, n=16 mice/group, p&lt;0.0001). About 76 % of OB hearts showed afterdepolarizations and fibrillation vs no events in lean. APD50 and APD90 significantly decreased as stimulation frequency increased from 4 to 14 Hz in OB hearts vs lean (n=6 mice/group, p&lt;0.05). Peak CaT from OB hearts were significantly decreased compared to peak CaT from lean (0.3±0.05 vs. 0.8±0.06, n=9, p&lt;0.001). CICR gain in OB hearts was also significantly compromised compared to lean (5.2±1 vs 23.3±1.4, n=7 mice/group, p&lt;0.0001). After WL, OB mice showed a decreased AF burden (21.7±8 s), increased APD, increased peak CaT (0.8±0.15) and increased CICR gain (20±2.3) back to lean levels (n=8, p&lt;0.001). In conclusion, shortened APs, spontaneous afterdepolarizations and impaired CICR significantly contribute to the development of AF in OB. WL reversed the electrical phenotype and the impaired Ca 2+ dynamics and prevented AF.
Abstract 13332: Obesity Paradox in Stress Cardiomyopathy When Comparing Outcomes
Authors: Lily N Dastmalchi, Matthew S Delfiner, Estefania Oliveros
Journal: Circulation (2022)

Introduction:Stress Cardiomyopathy (SCM), is an acute reversible myocardial injury associated with transient left ventricular dysfunction. Risk factors include female sex, post-menopause, anxiety, depression, schizophrenia, asthma and chronic obstructive pulmonary disease, diabetes, and substance use. Obesity has an increased sympathetic tone and state of chronic metabolic stress, both of which are similar in etiology to SCM. We postulate that obesity may have high prevalence in patients with SCM. Methods: We queried the Nationwide Inpatient Sample database (2016-2019) to identify adult patients with SCM with and without obesity, along with other common co-morbidities using ICD-10 codes. We compared the categorical and continuous variables by Pearson χ2 and Student t test. Results: There were 31,725 patients with SCM. The mean age was 67.15 + 14 years and the population was predominately female, n=26409 (83.2%). Racial distribution consisted of White (n=24713 77.9%), Black (n=24713, 8%), and Hispanic (n=1918, 6%). There were 3816 (12%) who were diagnosed with obesity. When comparing both groups, obese patients were found to be younger than non-obese, 63.3 + 14 years vs. 67.68 + 13 years, p&lt;0.001, respectively. Obese patients had higher incidences of hypertension (n=10317; 38.9% vs. 1485; 37%, p=0.005), chronic kidney disease (n=3874; 17.5% vs. n=668; 13.9%, p&lt;0.001), dyslipidemia (n=1771; 46.4% vs. n=10625; 38.1%, p &lt;0.001), diabetes mellitus (n=373; 9.8% vs n=1278; 4.6%, p&lt;0.001), non-alcoholic fatty liver disease (n=30; 0.8% vs. n=68; 0.2%, p&lt;0.001), and polycystic ovarian syndrome (n= 30; 0.8% vs n=68; 0.2%, p&lt;0.001). Tobacco use was higher in non-obese vs. obese patients (n=311; 1.1% vs. 28; 0.7%, p=0.32). The length of stay for both groups was similar, 7-days. Obese patients had a lower total hospital charges ($95,098 vs. $98,735). There was a lower incidence of mortality among obese patients n=194 (5.1%) vs. non-obese n=1743 (6.2%), p&lt;0.005. Conclusion: Despite obese patients having more risk factors for developing SCM than non-obese patients, they were found to have decreased mortality and a lower cost of stay. These findings suggest that obesity may play a paradoxical role in SCM.
Abstract 14332: Syncope, Storm, and Shock: Fulminant Myocarditis
Authors: Nikhil Gandhi, Jordan Swisher, Yazan Alkehef, Hiroshi Yamasaki
Journal: Circulation (2022)

A 46-year-old female with prediabetes and recent hysterectomy three weeks prior presented to the hospital for syncope. Patient reported no chest pain or dyspnea but complained of intermittent palpitations. The patient developed runs of non-sustained ventricular tachycardia which quickly escalated into incessant ventricular tachycardia (VT). Unresponsive to maximal medical therapy, the patient was cardioverted, intubated and sedated. Electrocardiogram was obtained which showed ST segment elevation in V1 and V2 without reciprocal changes. Bedside point-of-care ultrasound was negative for wall motion abnormalities. Laboratory results were significant for normal electrolytes, elevated troponins peaking at 7.14 ng/mL the following morning, and lactic acid of 3.2 mmol/L. Patient was initiated on vasopressor and ionotropic support for suspected shock. Left heart catheterization was negative for obstructive coronary artery disease. Right heart catheterization revealed mild pulmonary hypertension and biventricular failure. Formal echocardiogram revealed mid-range ejection fraction with a small pericardial effusion. The patient’s clinical status was deteriorating and revealed multiorgan failure. In conjunction with advanced heart failure and mechanical circulatory support teams, veno-arterial extracorporeal membrane oxygenation was initiated with subsequent implantation of intra-aortic balloon pump. High-dose steroids were given while awaiting transfer to a quaternary center. The patient is currently being evaluated for endomyocardial biopsy and evaluation of left ventricular assist device or heart transplantation due to fulminant myocarditis (FM). FM requires early recognition, intensive support, and further investigation for optimal management.
Abstract 13051: Comparative Antiplatelet Effects of Chlorthalidone and Hydrochlorothiazide
Authors: Anirudh Palicherla, Mahmoud Ismayl, Khalid M Bashir, Tammy Burns, Samuel J Pirruccello, Sarah Aurit, Daniel E Hilleman
Journal: Circulation (2022)

Introduction: The ACC/AHA hypertension guidelines recommended chlorthalidone (CTD) over hydrochlorothiazide (HCTZ) due to its longer half-life and proven reduction in major adverse cardiovascular events. The mechanism of the potential benefit of CTD compared to HCTZ has not been established. Unlike other thiazide diuretics, studies suggest that CTD may affect platelet aggregation, gene transcription, angiogenesis, and vascular permeability. We aimed to compare the antiplatelet effects of CTD versus HCTZ. Methods: We conducted a prospective, double-blind, randomized, three-way crossover study comparing the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers ≥ 19 years of age. ASA was included in the study as a known control for inhibition of platelet aggregation. Whole blood aggregometry was used to assess the impact of treatments on platelet activation and aggregation. Results: Of the 40 subjects, 34 (85%) completed the 3-way crossover comparison. Six subjects were excluded due to non-compliance and adverse effects. Compared to ASA, both CTD and HCTZ had no antiplatelet effects (Table 1). There was no statistically significant difference between CTD and HCTZ in terms of platelet function. Conclusions: Although recent studies showed increased cardiovascular benefit with CTD compared to HCTZ, CTD and HCTZ do not have antiplatelet effects. Larger studies are needed to confirm our findings.
Abstract 13073: Antisense Transcripts Regulate Titin Alternative Splicing and Sarcomere Function in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Selvi Celik, Ludvig Hyrefelt, Tomasz Czuba, Oscar Andre, Lovisa Lindquist, Mario Grossi, Pontus Nordenfelt, Gustav Smith, Olof Gidlof
Journal: Circulation (2022)

The giant protein Titin is an essential structural component of the sarcomere and a key determinant of passive tension during diastole. Titin tension is regulated by alternative splicing within the spring-like domains in the I-band region of TTN pre-mRNA. The cardiac RNA-binding protein RBM20 has been shown to promote TTN exon skipping during splicing, but additional factors are likely involved. We hypothesized that a natural antisense transcript in the TTN locus ( TTN-AS1 ) could regulate TTN splicing in cis through recruitment of spliceosome components. Through single nuclei RNA-Seq and RNA fluorescence in situ hybridization (ISH) on human cardiac tissue and iPS-derived cardiomyocytes (iPS-CM), we showed that the expression of TTN-AS1 was restricted to cardiomyocyte nuclei. The percent spliced in (PSI) of each TTN exon was calculated based on RNA-Seq data from iPS-CM (n=3) and 26 exons (all in the I-band region) that are normally spliced out were included to a significantly higher extent (adjusted p&lt;0.05) upon siRNA-mediated TTN-AS1 knock down. Reduced exon skipping from TTN exon 50 was confirmed with exon-junction spanning qPCR probes (p&lt;0.05, n=3). Similar effects on splicing were seen in cells where RBM20 had been knocked down. The consequences of TTN-AS1 knock down on cardiomyocyte contractile function was assessed using sarcomere tracking. Transgenic expression of ACTN2-GFP was used to visualize z-disks in iPS-CM, sarcomeres (n=14,636) were recorded during contractions using wide-field epifluorescence microscopy and analyzed using Sarc-Graph software. The analysis revealed that in cells where TTN-AS1 had been knocked down, sarcomere length and fractional shortening, as well as contraction and relaxation time were increased (all p&lt;0.001). Again, similar effects were seen in iPS-CM where RBM20 had been knocked down. We observed co-localization of TTN-AS1 and RBM20 protein during active TTN splicing in iPS-CM nuclei using multiplex RNA ISH and immunofluorescence and confirmed interaction between TTN-AS1 and RBM20 using RNA Immunoprecipitation and qPCR. In conclusion, we show that TTN-AS1 can affect cardiomyocyte contractile properties and sarcomere dynamics through regulation of TTN alternative splicing.
Abstract 14253: Distance to Cardiac Rehabilitation is Associated With Participation and Completion
Authors: Vinay Guduguntla, Hechuan Hou, Donald S Likosky, Francis D Pagani, Jeffrey McCullough, Steven J KETEYIAN, Devraj Sukul, Mike P Thompson
Journal: Circulation (2022)

Background: Despite the known benefits for patients undergoing coronary revascularization, cardiac rehabilitation (CR) use remains low, with few studies evaluating geographic barriers to care. In this analysis, we examined geographic access (i.e. distance) to a CR facility and its relationship to CR participation and completion. Methods: A cohort of 414,730 Medicare beneficiaries with coronary revascularization were identified from 2016-2018. Geographic access was defined as the presence of a CR facility within the beneficiary’s home zip code (yes vs. no) and the distance to the nearest CR facility: within the same zip code (0 miles), 0-10 miles, 10-20 miles, 20+ miles. We then used claims data to determine any CR participation within one year of discharge and completion of the full CR program (36 sessions). Multivariable logistic regression was used to identify the relationships, adjusting for patient factors. Results: A total of 155,872 (37.6%) beneficiaries participated in CR during the study period, with 45,591 (29.3%) completing 36 sessions. Nearly a quarter of beneficiaries had a CR facility located within their residential zip code (23.7%), with the majority of beneficiaries having a CR facility within 10 miles of the center of their home zip code ( Table 1). Beneficiaries without a CR facility in their zip code were more likely to be younger in age, men, non-white race categories, dual eligible for Medicare/Medicaid, and increasingly comorbid. Adjusting for patient factors, increasing distance category was associated with an absolute reduction in CR participation and completion (Table 1) . Conclusions: Distance to the nearest CR facility is an important predictor of CR participation and completion, with overall use declining as distance increased. Interventions to address geographic barriers, such as transportation programs or virtual/hybrid CR, may be necessary to improve CR participation in areas with limited facility access.